Foxo1 directly regulates the transcription of recombination-activating genes during B cell development (original) (raw)

Regulated expression of the recombinase RAG-1 and RAG-2 proteins is necessary for generating the vast repertoire of antigen receptors essential for adaptive immunity. Here, a retroviral cDNA library screen showed that the stress-regulated protein GADD45a activated transcription of the genes encoding RAG-1 and RAG-2 in transformed pro-B cells by a pathway requiring the transcription factor Foxo1. Foxo1 directly activated transcription of the Rag1-Rag2 locus throughout early B cell development, and a decrease in Foxo1 protein diminished the induction of Rag1 and Rag2 transcription in a model of receptor editing. We also found that transcription of Rag1 and Rag2 was repressed at the pro-B cell and immature B cell stages by the kinase Akt through its 'antagonism' of Foxo1 function. Thus, Foxo1 is a key regulator of Rag1 and Rag2 transcription in primary B cells. Adaptive immunity depends on the concerted action of the lymphocyte-restricted products of recombination-activating gene 1 (RAG-1; A002009) and recombination-activating gene 2 (RAG-2; A002010), which catalyze the somatic DNA rearrangement of variable, diversity and joining gene segments forming the variable-domain exons of B cell antigen receptors (BCRs) and T cell antigen receptors (TCRs) 1. In B cells, RAG activity occurs in two discrete waves: first at the common lymphoid progenitor and pro-B cell stages during immunoglobulin heavychain locus rearrangement and then again at the pre-B cell stage during immunoglobulin lightchain locus rearrangement 2,3. Productive rearrangement of both heavy-and light-chain genes leads to BCR expression at the immature B cell stage. Basal signaling from a self-tolerant BCR limits RAG activity at this stage and ultimately leads to complete loss of expression of the genes encoding RAG-1 and RAG-2 (Rag1 and Rag2, respectively; collectively called 'Rag' here) as B cells mature further 4. If, however, the BCR recognizes self antigen, development halts and Rag expression continues, resulting in further light-chain locus rearrangement (receptor editing) and altered BCR specificity until an 'innocuous' BCR is expressed or the potential for light-chain gene recombination is exhausted 5,6. Regulated expression of RAG-1 and RAG-2 in B cells is thus necessary for both the nearly limitless repertoire of antigen receptors as well as the 'pruning' of this repertoire to maintain central tolerance. Both the pre-BCR and BCR form signaling complexes that suppress Rag transcription at critical stages of B cell development 4,7,8. This negative-feedback regulation of RAG activity by the products of recombination prevents genomic instability in large cycling pre-B cells, contributes to allelic exclusion of heavy-and light-chain expression and inactivates variable-(diversity)

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